Nitric oxide provider (NO Provider) is a kind of prodrugs that are capable of releasing NO in vivo. It refers to a drug that produces NO per se or by interacting with other substances, without catalyzed by nitric oxide synthase (NOS). It may act as a transportation form as well as a storage form of NO in vivo. It extends the half-life of NO, and overcomes inconveniences caused by inhaling NO and the disadvantage of difficulty in controlling the amount of the inhaled NO. NO provider-type drugs are prodrugs mainly made by binding a mother nucleus, which is the structure of known drugs or active compounds, to the NO provider through various linking groups. They can release the original drug and NO through relevant enzymatic or non-enzymatic action in vivo. Studies have shown that due to the effect of releasing NO, the efficacy of the NO provider-type drug is generally better than the original drug, and the adverse reaction is significantly less than the original drug.
At present, the trend of researching NO provider-type drugs is binding the NO provider to the effective drug by using the principle of the prodrug to form a new bound drug which is more effective. The advantages of this drug design manner consist in improving the bioavailability of the drugs, increasing the stability of the drugs, reducing toxic and side effects, and prolonging the efficacy of the drugs, etc. At the same time, it has the features of NO provider, and provides a biological activity depending on NO. The research on NO providers has become one of the hot spots and frontiers in the fields of biomedicine and pharmacy in recent years.
Cardiovascular diseases have been a worldwide public health concern. According to the statistics, about 3.5 million people die of cardiovascular diseases every year, i.e., one person die of cardiovascular diseases every 10 seconds. Fat metabolism or abnormal functioning in human body results in hyperlipidemia. Hyperlipidemia can directly induce some diseases that severely harm human health, such as atherosclerosis. Hyperlipidemia can cause insufficient blood supply to human tissues and organs, thereby inducing cardiovascular and cerebrovascular diseases such as coronary heart disease, cerebral stroke, hypertension, and renal failure. The mechanism of reverse cholesterol transport (RCT) in human body can ameliorate hyperlipidemia. RCT is a normal physiological process that can transport atherosclerotic plaques out of the arteries and eliminate it from the body through liver.
Apolipoprotein A-I (ApoA-I) is an important component of functional high density lipoprotein (HDL) particulates. ApoA-I can promote RCT, effectively eliminate atherosclerotic plaques, prevent and treat hyperlipidemia. On the other hand, ApoA-I can also activate phosphorylated acetyl coenzyme carboxylase by activating AMPK signal pathway, improve the absorption of glucose in muscle cells, and ameliorate blood glucose metabolism in vivo. With further researches, it is found that ApoA-I not only relates to the regulation of lipid and blood glucose metabolism in vivo, but also closely relates to immune function and neurological function. Clinical experimental data shows that a low level of ApoA-I in vivo can lead to increased incidences of cardiovascular diseases. Therefore, increasing the content of ApoA-I in human body will play an active role in preventing and treating cardiovascular diseases.
The development of small molecule compounds that increase the level of ApoA-I in vivo has become an important direction in the development of therapeutic drugs for cardiovascular diseases. This kind of small molecule compounds are disclosed in patents of WO 2006/045096, WO 2008/092231, and WO 2010/123975, etc.